Current activities within the Center for research on genomics and global health (CRGGH) builds on the more than two decades of research dedicated to investigating the pathogenesis of metabolic disorders, with attention to health disparities (HD). An overarching concern of CRGGH investigators is that health inequities between ethnic groups within the US and between developed and developing countries will widen if these populations are not fully involved in genomic science. Estimates of the proportion of genomic research conducted in diverse populations are discouraging, with over 90% of GWAS focusing on those of European descent. The notion that these findings will be broadly applicable to all global populations is flawed given findings of ethnic-specific risk variants and significant inter-ethnic differences in allele frequencies across the genome, as demonstrated by the wide variation in GWAS-associated variants across populations. We and others have demonstrated that genetic ancestry can be leveraged in the search for genetic risk variants and for improving clinical care. Thus, CRGGH investigators are committed to conducting original research in diverse ancestral populations, developing publicly-available international genomic resources and analytical tools to increase trans-ethnic gene mapping, and to train scientists from diverse ethnic backgrounds (see the mission statement at http://crggh.nih.gov/mission.cfm). As these goals are multi-faceted, we take advantage of a variety of strategies across the breadth of the research spectrum, incorporating new advances, such as integration of omics data and CRISPR/Cas9 technology, into the Centers work. We advanced our science by developing and participating in the development of several active protocols including: 1) H3Africa Multi-Centre Study of the Prevalence and Environmental and Genetic Determinants of T2D in Africa (11 sites in 8 countries to recruit 6,000 cases and 6,000 controls); 2) Investigation of the Pathogenesis of Podoconiosis using RNA-seq and immunologic approaches (Ethiopia); 3) Genetics of T2D in Diverse Populations (African ancestry individuals); 4) Genetics of T2D among Han Chinese; 5) Genetics of Obesity, Diabetes, and Heart Disease in African Diaspora Populations (AA and recent African immigrants); 6) Genomics, Environmental Factors and Social Determinants of Cardiovascular Disease in AA; 7) Active leadership and analyst roles in the multi-ethnic CHARGE Gene x Lifestyle Working Group; 8) Global Human Ancestry (5,966 genotyped individuals in 282 samples from global ethno-linguistic groups); 9) Advanced genetic analyses of dbGaP datasets for the study of complex traits; and 11) continued participation in the 1000 Genomes Project, which led to a Nature publication A global reference for human genetic variation55. 12) We continue to play a leadership role in the implementation of the H3Africa initiative, including the design of a custom chip array and our publication of the first H3Africa consortium paper, Enabling the genomic revolution in Africa in Science. 13) We are a member of the Consortium on Asthma among African ancestry Populations in the Americas (CAAPA) that developed the African Power Chip for the identification of risk variants for asthma and other complex traits. This work contributed to the development of the Multi-Ethnic Genotyping Array (MEGA). As part of CAAPA, we are conducting a clinical study of Asthma entitled New Approaches for Empowering Studies of Asthma in Populations of African Descent at the NIH clinical center in Bethesda, MD. Dyslipidemia: As part of the CHARGE Consortium, we lead the Multi-ancestry genome-wide gene-smoking interaction study of 387,272 individuals that identified 13 new gene regions associated with serum lipids. Several of these novel discoveries were in African Americans emphasizing the need for more genomic studies different ancestral populations. Hypertension and related traits: a) In our African American project (HUFS), we showed that boys who grew up in two-parent homes are less likely to have elevated BP and HTN as adults compared to those raised by a single or neither parent. This is the first AA study to document an association between childhood family living arrangements and BP56. b) We contributed to the identification of novel variants (in EVX1-HOXA, RSPO3, and PLEKHG1) influencing BP and HTN susceptibility in AA57. Diabetes and related traits: a) We reported the largest genomic study of type 2 diabetes (T2D) in sub-Saharan Africans, having studied 5231 individuals from Nigeria, Ghana and Kenya. We identified known genomic variants and linked a novel gene ZRANB3 to the development of T2D (Nature Communications 2019). We used gene editing tools (CRISPR-Cas9 system) to knockout ZRANB3 in zebrafish, hence making the gene inoperative. We also created another zebrafish model where we used biological tools to reduce the expression of the ZRANB3 gene. In both cases, we observed a reduction in -cell numbers in the developing zebrafish embryo. Through further assessment, we realized it was because the -cells were being destroyed. To follow up on these results and identify the consequence of such -cell death, we took -cell cells from mice and performed a similar knockdown of the ZRANB3 gene as in the zebrafish model. We found that cells with ZRANB3 knockdown released much less insulin in the presence of high glucose than normal mice -cells. We also used transcriptomics of visceral adipose tissue from AA to profile differentially-expressed genes in T2D associated with morbid obesity. We detected 68 differentially expressed genes, including MYO10, which encodes an actin-based motor protein that has been associated with T2D. Our upstream regulator analysis predicted five miRNAs as regulators of the expression changes. d) We used shotgun proteomics to dissect the molecular mechanism underlying the metabolically healthy but obese (MHO) phenotype (obese people without comorbidities like diabetes, dyslipidemia or hypertension) in contrast to the metabolically abnormal obese phenotype (MAO). Genomics of neglected and rare diseases: Our 2012 NEJM publication shed light on the genetic basis of podoconiosis, a neglected tropical endemic non-filarial elephantiasis, and our research also led to the clinical staging of the disease. We discovered two novel missense mutations in BBS5 with pathogenic properties and implications for screening for Bardet-Biedl syndrome in Africans. We were lead authors on the first publication of the AGVP, which found novel evidence of complex, regionally distinct hunter-gatherer and Eurasian admixture across sub-Saharan Africa and demonstrated improved imputation accuracy and presented an efficient genotype array design for GWAS in Africans. -Saharan Africa. We investigated ancestry of 3,528 modern humans from 163 global samples and identified 19 ancestral components, with 94.4% of individuals showing mixed ancestry; the ubiquity of mixed ancestry underscores the importance of accounting for ancestry in history, forensics, health, and drug labeling. Lastly, our recent research into the origin of the sickle mutation attracted international interests. Briefly, inheriting two copies of a hemoglobin gene carrying the sickle mutation leads to a painful condition called sickle cell disease, which historically was fatal during childhood. However, inheriting only one copy of the mutant hemoglobin gene leads to protection against malaria, which kills 400,000 people each year. By surveying the genomes of 2,932 people from around the world, we found that 156 individuals who carried one copy of the sickle cell mutation inherited the same mutation from a single person who lived approximately 7,300 years ago. We also identified 27 other mutations that tend to be inherited with the sickle mutation. One or more of these other mutations ma